Mitochondrial protection against excessive superoxide production involves an elaborate antioxidant defense system, including that associated with manganese superoxide dismutase (MnSOD). Notably, MnSOD confined to mitochondria but not MnSOD genetically manipulated to be in the cytosol attenuates radiation induced cellular damage [2]. There are at least three possible ways to enhance MnSOD activity in the mitochondria: i) increase expression of the enzyme; ii) stabilize the enzyme against inactivation and prolong its life-time; iii) utilize SOD mimetics that are targeted to mitochondria. Increased expression of MnSOD has been shown to be radioprotective and this can be attained by gene therapy [3, 4] or by thiol compounds (such as WR-1065-the active thiol form of amitostine or N-acetly-cysteine) [5-7]. We have demonstrated significant radiation protection in rodent lung, esophagus, oral cavity, and intestine [3, 8-10] as well as after total-body irradiation (TBI) [11] by overexpression of MnSOD transgene prior to or after irradiation. However, gene therapy approaches will be difficult to administer to mass number of victims during a nuclear and radiological attack or accident. Therefore, we here propose to employ stabilized inactivation-resistant MnSOD and mitochondria targeted SOD mimetics as novel optimized mechanism-based radiomitigation strategies.